Processing of pro-hormone precursor proteins

Harris, Robert B.

doi:10.1016/0003-9861(89)90379-2

Cited by 87 publications

(58 citation statements)

References 124 publications

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“…Numerous protein and peptide hormones, including insulin, glucagon, and adipocytokines such as tumor necrosis factor-␣ and adiponectin, are proteolytically cleaved to generate the smaller functional form of the protein. The most common processing recognition site in prohormones consists of a doublet of basic amino acids (33), which is recognized by subtilisin-like proprotein convertases, although other types of motifs are also possible. Carboxypeptidase E is responsible for the removal of carboxyl-terminal basic residues exposed by the endoproteases (34).…”

Section: Discussionmentioning

confidence: 99%

The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment

Mandard

Zandbergen

Tan

et al. 2004

Journal of Biological Chemistry

246

256

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The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor ␣ (PPAR␣) and PPAR␤/␦ agonists in rat and human hepatoma cell lines and by PPAR␥ and PPAR␤/␦ agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPAR␣ agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form.

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Section: Discussionmentioning

confidence: 99%

The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment

Mandard

Zandbergen

Tan

et al. 2004

Journal of Biological Chemistry

246

256

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“…It has long been known that pyroglutamate residues are spontaneously formed from glutamine after cleavage of basicamino-acid doublets adjacent to the C-terminus of a precursor peptide, and that the recognition site for this cleavage usually involves a strongly polar residue such as Glu or Asp adjacent to the basic-amino-acid doublet [28]. For C. maenas CHH-11, it is established that the only precursor is a 38-amino-acid peptide (CHH-precursor-related peptide) of unknown function, which is separated from CHH by a Glu-Lys-Arg sequence [29].…”

Section: Discussionmentioning

confidence: 99%

Does the N‐Terminal Pyroglutamate Residue have Any Physiological Significance for Crab Hyperglycemic Neuropeptides?

Chung

Webster

1996

European Journal of Biochemistry

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A characteristic feature of all crustacean hyperglycemic hormones (CHH) is that they are always present in the sinus gland as multiple forms or isoforms. The amino acid sequence of the minor form of CHH from the green shore crab, Curcinus maenas, was determined by automated microsequencing and MS, and was almost identical to that of the major form, except that the N-terminal residue was glutamine rather than pyroglutamate. Limited analysis (electrospray MS and amino acid composition) of the two corresponding forms of CHH from the edible crab, Cancer pugurus, suggested a similar phenomenon in this species. For C. muenus, both forms were indistinguishable in terms of their ability to cause sustained hyperglycemia in vivo and repression of ecdysteroid synthesis in vitro. Similarly, the two forms were immunologically identical in RIA, and exhibited similar binding characteristics in competitive-receptorbinding assays. CD studies showed only minor differences in presumed secondary structure. In vitro release experiments with isolated sinus glands demonstrated that both forms are probably released in a stoichiometric manner and that both peptides are present in the haemolymph at the same ratio as that in the sinus gland. Preliminary results suggest that the in vivo clearance/degradation rates of both peptides are similar. The unblocked (Gln) terminus is of particular significance, since the presence of this amino acid indicates that this peptide is derived from a precursor that does not possess the same structure of those of established preproCHH, or that N-terminal processing is slow, which results in the presence of unblocked CHH in sinus glands. The similar biological activity of the unblocked CHH to that of the blocked CHH suggests that the N-terminal pyroglutamate residue has no obvious biological significance (with respect to the known functions of CHH), an observation which is in contrast to the widely accepted paradigms concerning the stability and biological activity of N-terminally blocked and unblocked peptides.Keywords: crustacean hyperglycemic hormone ; isoform; pyroglutamate ; crab.In decapod crustaceans, many structurally related neurohormones, which are synthesised by neurosecretory cells in the Xorgan of the eyestalk and released from a neurohaemal tissue, the sinus gland, have been identified and fully characterised in terms of amino acid sequence by means of sequence analysis and cDNA-cloning strategies [I -61. These have been functionally identified as hyperglycemic hormones (CHH), moult-inhibiting hormones, vitellogenesis/gonad-inhibiting hormones and mandibular-organ-inhibiting hormones, and evidence suggests that several of these hormones may be multifunctional [7]. With particular regard to the hormones primarily identified as CHH, (based upon their ability to profoundly elevate haemolymph glucose levels in vivo), it has long been apparent thatmultiple forms (2-4 peaks are separable by HPLC) of CHH peptides are found in the sinus gland of all decapods examined [8-lo]. In astacurans (crayfish an...

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“…Serine-, cysteinyl-, aspartyl-, and metalloproteases have all been identified as processing enzymes responsible for the conversion of precursor proteins to bioactive peptides in mammalian cells (9). In their original report on the isolation and characterization of ET, Yanagisawa and coworkers (1) speculated that ECE is a serine protease with a chymotrypsinlike specificity.…”

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confidence: 99%

Phosphoramidon blocks the pressor activity of porcine big endothelin-1-(1-39) in vivo and conversion of big endothelin-1-(1-39) to endothelin-1-(1-21) in vitro.

McMahon¹,

Palomo²,

Moore³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

152

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In porcine aortic endothelial cells, the 21-amino acid peptide endothelin-1 (ET-1) is formed from a 39-amino acid intermediate called "big endothelin-1" (big ET-1) by a putative ET-converting enzyme (ECE) that cleaves the 39-mer at the bond between Trp-21 and Val-22. Since big ET-1 has only 1/100-1/150th the contractile activity of ET-1, inhibition of ECE should effectively block the biological effects of ET-1. Big ET-1 injected intravenously into anesthetized rats produces a sustained pressor response that presumably is due to conversion of big ET-1 into ET-1 by ECE. We determined the type of protease activity responsible for this conversion by evaluating the effectiveness of protease inhibitors in blocking the pressor response to big ET-1 in ganglion-blocked anesthetized rats. The serine protease inhibitor leupeptin, the cysteinyl protease inhibitor E-64, and the metalloprotease inhibitors captopril and kelatorphan were all ineffective at blocking the pressor response to big ET-1. However, the metalloprotease inhibitors phosphoramidon and thiorphan dose-dependently inhibited the pressor response to big ET-1, although phosphoramidon was substantially more potent than thiorphan. None of the inhibitors blocked the pressor response to ET-1 and none had any effect on mean arterial pressure when administered alone. In a rabbit lung membrane preparation, ECE activity was identified that was blocked by the metalloprotease inhibitors phosphoramidon and 1,10-phenanthroline in a concentration-dependent manner. This enzyme converted big ET-1 to a species of ET that comigrated on HPLC with ET-1 and produced an ET-like contraction in isolated rat aortic rings. Our results suggest that the physiologically relevant ECE is a metalloprotease.In 1988, Yanagisawa and coworkers (1) reported on the isolation and characterization of a peptide, endothelin (ET), from the culture supernatant of porcine aortic endothelial cells. Now referred to as endothelin-1 (ET-1), this peptide contracts vascular smooth muscle in vitro and produces a sustained pressor response in vivo. In porcine aortic endothelial cells, the 21-amino acid peptide ET-1 is formed from a 39-amino acid intermediate called "big endothelin-1" (big ET-1) by a putative ET-converting enzyme (ECE) that hydrolyzes the 39-mer at the bond between Trp-21 and Val-22 to yield ET-1-(1-21) and the C-terminal fragment, big ET-1-(22-39) (2). Since big ET-1 has only 1/100-1/150th the contractile activity of ET-1 (3), inhibition of ECE should effectively block the biological effects of ET-1. This could be an important therapeutic strategy for the treatment of hypertension, acute renal failure, myocardial infarction, and coronary and cerebral vasospasm-diseases in which an overproduction of ET might play an important pathophysiological role (4-8).Serine-, cysteinyl-, aspartyl-, and metalloproteases have all been identified as processing enzymes responsible for the conversion of precursor proteins to bioactive peptides in mammalian cells (9). In their original report on the isolati...

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Processing of pro-hormone precursor proteins

Cited by 87 publications

References 124 publications

The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment

The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment

Does the N‐Terminal Pyroglutamate Residue have Any Physiological Significance for Crab Hyperglycemic Neuropeptides?

Phosphoramidon blocks the pressor activity of porcine big endothelin-1-(1-39) in vivo and conversion of big endothelin-1-(1-39) to endothelin-1-(1-21) in vitro.

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